Piperidine derivatives and process for their production

ABSTRACT

The present invention relates to substantially pure piperidine derivative compounds of the formulae:  
                 
 
     wherein  
     R 1  is hydrogen or hydroxy;  
     R 2  is hydrogen;  
     or R 1  and R 2  taken together form a second bond between the carbon atoms bearing R 1  and R 2 ;  
     R 3  is —COOH or —COOR 4 ;  
     R 4  has 1 to 6 carbon atoms;  
     A, B, and D are the substituents of their respective rings each of which may be different or the same and are hydrogen, halogens, alkyl, hydroxy, alkoxy, or other substituents.  
     A process of preparing such piperidine derivative compounds in substantially pure form is also disclosed.

FIELD OF THE INVENTION

[0001] The present invention relates to piperidine derivatives and aprocess for their production.

BACKGROUND OF THE INVENTION

[0002] Terfenadine,1-(p-tert-butylphenyl)-4-[4′-(α-hydroxydiphenylmethyl)-1′-piperidinyl]-butanolis a non-sedating anti-histamine. It is reported to be a specificH₂-receptor antagonist that is also devoid of any anticholingeric,anti-serotoninergic, and anti-adrenergic effects both in vitro and invivo. See D. McTavish, K. L. Goa, N. E. Ferrill, Drugs 1990, 39, 552; C.R. Kingsolving, N. L. Monroe, A. A. Carr, Pharmacologist. 1973, 15, 221;J. K. Woodward, N. L. Munro, Arzneim-Forsch, 1982, 32,1154; K. V. Mann,K. J. Tietze, Clin. Pharm. 1989, 6, 331. A great deal of effort has beenmade investigating structure-activity relationships of terfenadineanalogs, and this is reflected in the large number of U.S. patentsdisclosing this compound and related structures as follows:

[0003] U.S. Pat. No. 3,687,956,to Zivkovic

[0004] U.S. Pat. No. 3,806,526 to Carr, et. al.

[0005] U.S. Pat. No. 3,829,433 to Carr, et. al.

[0006] U.S. Pat. No. 3,862,173 to Carr, et. al.

[0007] U.S. Pat. No. 3,878,217 to Carr, et. al.

[0008] U.S. Pat. No. 3,922,276 to Duncan, et. al.

[0009] U.S. Pat. No. 3,931,197 to Carr, et. al.

[0010] U.S. Pat. No. 3,941,795 to Carr, et. al.

[0011] U.S. Pat. No. 3,946,;022 to Carr, et. al.

[0012] U.S. Pat. No. 3,956,296 to Duncan, et. al.

[0013] U.S. Pat. No. 3,965,257 to Carr, et. al.

[0014] U.S. Pat. No. 4,742,175 to Fawcett, et. al.

[0015] Terfenadine has been linked to potentially fatal abnormal heartrhythms in some patients with liver disease or who also take theantifungal drug ketoconazole or the antibiotic erythromycin. In animaland human metabolic studies, terfenadine was shown to undergo highfirst-pass effect, which results in readily measurable plasmaconcentrations of the major metabolite4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylphenylaceticacid, also known as terfenadine carboxylic acid metabolite. Theterfenadine carboxylic acid metabolite also possesses anti-histaminicactivity in animal models and may lack the cardiac side effects seenwith terfenadine.

[0016] Piperidine derivatives related to the terfenadine carboxylic acidmetabolite are disclosed in the following U.S. patents:

[0017] U.S. Pat. No. 4,254,129 to Carr, et. al.

[0018] U.S. Pat. No. 4,254,130 to Carr, et. al.

[0019] U.S. Pat. No. 4,285,957 to Carr, et. al.

[0020] U.S. Pat. No. 4,285,958 to Carr, et. al.

[0021] In these patents,4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid and related compounds are prepared by alkylation of a substitutedpiperidine derivative of the formula:

[0022] with an ω-haloalkyl substituted phenyl ketone of the formula:

[0023] wherein the substituents halo, R₁, R₂, n, z, and R₆ are describedin column 6 of U.S. Pat. No. 4,254,130.

[0024] It is further described that the ω-haloalkyl substituted phenylketone wherein Z is hydrogen are prepared by reacting an appropriatestraight or branched lower alkyl C₁₋₆ ester of α,α-dimethylphenylaceticacid with the compound of the following formula:

[0025] under the general conditions of a Friedel-Crafts acylation,wherein halo and m are described in column 11 of U.S. Pat. No.4,254,129. The reaction is carried out in carbon disulfide as thepreferred solvent.

[0026] Applicant has discovered that the preparation of ethyl4-(4-chloro-1-oxobutyl)-α,α-dimethylphenylacetate by reaction of4-chlorobutyryl chloride, aluminum chloride, and ethylα,α-dimethylphenylacetate in carbon disulfide, as described in Example 1of U.S. Pat. Nos. 4,254,130 and 4,285,958 provides an mixture ofmonosubstituted aromatic regioisomers of the formula:

[0027] wherein the chlorobutyryl substituent is attached at either ofthe three aromatic carbons which are meta or para to the dimethylacetatesubstituent. These regioisomers are not separable by standard techniquesof thin layer chromatography, or column chromatography, and low fieldproton nuclear magnetic resonance spectroscopy is inconclusive inidentifying the product of this reaction as a mixture. When the mixtureof monosubstituted aromatic regioisomers of the preceding formula isreacted with a piperidine of the formula:

[0028] a second mixture of aromatic regioisomers is obtained of theformula:

[0029] wherein the monosubstituted meta, para mixture of regioisomers isobtained.

[0030] It is known in the art that a monoalkyl substituent on a benzenering is ortho, para directing in electrophillic aromatic substitutionreactions such as a Friedel-Crafts reaction. Thus, it would be expectedthat the Friedel-Crafts reaction of α-chlorobutyryl chloride with ethylα,α-dimethylphenylacetate would yield predominantly the para substitutedproduct of the formula:

[0031] because of the electron donating, para-directing character of thedimethylalkyl substituent combined with the steric hindrance associatedwith reaction of the ortho positions. In practice, the inductiveelectronic withdrawing effect of the carboxylic ester of ethylα,α-dimethylphenylacetate counteracts the expected alkyl electrondonating effect, resulting in no significant directing effect for thearomatic substitution reaction. For the described reaction, astatistical mixture of meta to para regioisomers results, with the twometa positions predominating.

[0032] The above second mixture of regioisomers can be converted to athird mixture of regioisomers of formula:

[0033] Although the second mixture of regioisomers and the third mixtureof regioisomers can be analyzed by HPLC experiments, a practicalseparation to obtain gram quantities of substantially pure regioisomershas not been achieved. Each mixture (including the first), would beexpected to contain 33% of the para isomer and 67% of the meta isomer.Since these components are inseparable, it has not been possible toobtain either of the regioisomers in each mixture in substantially pureform.

SUMMARY OF THE INVENTION

[0034] The present invention relates to substantially pure piperidinederivative compounds of the formulae:

[0035] wherein

[0036] R₁ is hydrogen or hydroxy;

[0037] R₂ is hydrogen;

[0038] or R₁ and R₂ taken together form a second bond between the carbonatoms bearing R₁ and R₂;

[0039] R₃ is —COOH or —COOR₄;

[0040] R₄ is an alkyl with 1 to 6 carbon atoms;

[0041] A, B, and D are the substituents of their rings, each of whichmay be different or the same, and are selected from the group consistingof hydrogen, halogens, alkyl, hydroxy, alkoxy, or other substituents

[0042] or a salt thereof. These compounds are useful in pharmaceuticalcompositions, particularly as antihistamines, antiallergy agents, andbronchodilators.

[0043] The piperidine derivative compound is prepared by a process whichis initiated by providing a substantially pure regioisomer of thefollowing formula:

[0044] The substantially pure regioisomer is converted to the piperidinederivative having a keto group with a piperidine compound of theformula:

[0045] A number of synthetic pathways for preparing the substantiallypure regioisomer and for reacting it with the piperidine compound havinga keto group are disclosed. The piperidine derivative having a ketogroup can be converted to the above piperidine derivative having ahydroxyl group by reduction.

[0046] Although a wide variety of piperidine derivatives can be producedby the process of the present invention, it is particularly useful informing a hydroxylated piperidine derivative of the formula:

[0047] Alternatively, the process of the present invention can be usedto produce a piperidine derivative with a keto group of the followingformula:

DETAILED DESCRIPTION OF THE INVENTION

[0048] The present invention relates to substantially pure piperidinederivative compounds of the formulae:

[0049] wherein

[0050] R₁ is hydrogen or hydroxy;

[0051] R₂ is hydrogen;

[0052] or R₁ and R₂ taken together form a second bond between the carbonatoms bearing R₁ and R₂;

[0053] R₃ is —COOH or —COOR₄;

[0054] R₄ is an alkyl with 1 to 6 carbon atoms;

[0055] A, B, and D are the substituents of their rings, each of whichmay be different or the same, and are selected from the group consistingof hydrogen, halogens, alkyl, hydroxy, alkoxy, or other substituents

[0056] or a salt thereof.

[0057] These substantially pure piperidine derivative compounds may bein the form of 4-diphenylmethylpiperidine derivatives represented by thefollowing formulae:

[0058] where A, B, D, R₃ are defined above. The substantially purepiperidine derivative compounds include4-(hydroxydiphenylmethyl)piperidine derivatives according to thefollowing formulae:

[0059] where A, B, D, R₃ are defined above. Another useful class ofpiperidine derivative compounds are 4-diphenylmethylenepiperidinederivatives in accordance with the following formulae:

[0060] where A, B, D, R₃ are defined above. Examples of R₄are straightor branched alkyl groups, including methyl, ethyl, n-propyl, isopropyl,n-butyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, and n-hexyl groups.

[0061] Illustrative examples of compounds of the present invention areas follows:

[0062]4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid;

[0063]4-[4-[4-(diphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid;

[0064]4-[4-[4-(diphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid;

[0065]4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethyl-3-hydroxybenzeneaceticacid;

[0066]4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethyl-2-hydroxybenzeneaceticacid;

[0067]4-[4-[4-(diphenylmethylene)-1-piperidinyl]-1-hydroxybutyl]-(α,α-dimethyl-3hydroxybenzeneaceticacid;

[0068]5-[4-[4-(diphenylmethylene)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid;

[0069] ethyl4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic;

[0070] n-pentyl4-[4-[4-(diphenylmethyl-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetate;

[0071] ethyl4-[4-[4-(diphenylmethylene)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetate;

[0072] methyl4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetate;

[0073] ethyl4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethyl-(3-hydroxybenzene)acetate;

[0074] n-propyl4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethyl-(2-hydroxybenzene)acetate;

[0075] n-hexyl4-[4-[4-(diphenylmethylene)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethyl-(3-hydroxybenzene)acetate;

[0076] ethyl5-[4-[4-(diphenylmethylene)-1-piperidinyl)-1-hydroxybutyl]-α,α-dimethylbenzeneacetate;

[0077] α,α-diphenyl-1-(4-(4-tert-butyl-2-hydroxyphenyl)hydroxybutylpiperidinemethanol;

[0078] α,α-phenyl-1-(4-(4-tert-butyl-3-hydroxy)phenyl)-4-hydroxybutylpiperidinemethanol;

[0079]α,α-diphenyl-1-(3-(4-tert-butyl-2-hydroxy)phenyl)-3-hydroxypropyl-4-piperidinemethanol;

[0080]α,α-diphenyl-1-(5-(4-tert-butyl-2-acetyloxy)phenyl)-5-hydroxypentyl-4-piperidinemethanol;

[0081] α,α-diphenyl-1-(4-(4-hydroxy-tert-butyl-2-hydroxy)-phenyl)-4hydroxybutyl-4-piperidinemethanol;

[0082]α,α-diphenyl-1-(4-(4-hydroxy-tert-butyl-3-hydroxy)-phenyl)-4-hydroxybutyl-4-piperidinemethanol;

[0083]α,α-diphenyl-1-(3-(4-hydroxy-tert-butyl-2-hydroxy)-phenyl)-3-hydroxybutyl-4-piperidinemethanol;

[0084]α,α-diphenyl-1-(4-(4-hydroxy-tert-butyl)phenyl)-4-hydroxybutyl-4-piperidinemethanol;

[0085]1-(4-tert-butyl-2-hydroxyphenyl)-4-(4-diphenylmethylene)-1-(piperidinyl)butanol;

[0086]1-(4-tert-butyl-3-hydroxyphenyl)-4-(4-diphenylmethylene)-1-(piperidinyl)butanol;

[0087]1-(4-tert-butyl-3-hydroxyphenyl)-2-(4-diphenylmethylene)-1-(piperidinyl)butanol;

[0088]1-(4tert-butyl-2-butyryloxyphenyl)-6-(4-(diphenylmethyl)-1-piperidinyl)hexanol;

[0089]1-(4-hydroxy-tert-butyl-2-hydroxyphenyl)-4-(4-(diphenylmethylene)-1-(piperidinyl)butanol;

[0090]1-(4-hydroxy-tert-butyl-3-hydroxyphenyl)-4-(4-(diphenylmethylene)-1-(piperidinyl)butanol;

[0091]1-(4-hydroxy-tert-butylphenyl)4-(4-(diphenylmethylene)-1-(piperidinyl)butanol;

[0092] Particularly preferred are compounds of the formulae:

[0093] Optionally, both diphenyl groups from the piperidine compound maybe alkyl (e.g., methyl) substituted at the position para to themethylene.

[0094] This invention also includes pharmaceutically acceptable salts inthe form of inorganic or organic acid or base addition salts of theabove compounds. Suitable inorganic acids are, for example,hydrochloric, hydrobromic, sulfuric, and phosphoric acids. Suitableorganic acids include carboxylic acids, such as, acetic, propionic,glycolic, lactic, pyruvic, malonic, succinic, fumaric, malic, tartaric,citric, cyclamic, ascorbic, maleic, hydroxymaleic, dihydroxymaleic,benzoic, phenylacetic, 4-aminobenzoic, anthranillic, cinnamic,salicyclic, 4-aminosalicyclic, 2-phenoxybenzoic, 2-acetoxybenzoic, andmandelic acid. Sulfonic acids, such as, methanesulfonic, ethanesulfonic,and β-hydroxyethane-sulfonic acid are also suitable acids. Non-toxicsalts of the compounds of the above-identified formulas formed withinorganic and organic bases include, for example, those alkali metals,such as, sodium, potassium, and lithium, alkaline earth metals, forexample, calcium and magnesium, light metals of group IIIA, for example,aluminum, organic amines, such as, primary, secondary, or tertiaryamines, for example, cyclohexylamine, ethylamine, pyridine,methylaminoethanol, and piperazine. These salts are prepared byconventional means, for example, by treating the piperidine derivativecompounds of the formula:

[0095] where R₁, R₂, and R₃ are defined above, with an appropriate acidor base.

[0096] The piperidine derivative compounds of the present invention canbe utilized as the biologically active components in pharmaceuticalcompositions. The compounds of this invention are useful asantihistamines, antiallergy agents, and bronchodilators. They may beadministered alone or with suitable pharmaceutical carriers, and can bein solid or liquid form such as, tablets, capsules, powders, solutions,suspensions or emulsions.

[0097] The compounds of this invention can be administered orally,parenterally, for example, subcutaneously, intravenously,intramuscularly, intraperitoneally, by intranasal instillation or byapplication to mucous membranes, such as, that of the nose, throat andbronchial tubes. Such application to mucous membranes can be achievedwith an aerosol spray containing small particles of a compound of thisinvention in a spray or dry powder form.

[0098] The quantity of the compound of the present inventionadministered will vary depending on the patient and the mode ofadministration and can be any effective amount. The quantity of thecompound administered may vary over a wide range to provide in a unitdosage an effective amount of from about 0.01 to 20 mg/kg of body weightof the patient per day to achieve the desired effect. For example, thedesired antihistamine, antiallergy, and bronchodilator effects can beobtained by consumption of a unit dosage form such as a tabletcontaining 1 to 50 mg of the compound of the present invention taken Ito 4 times daily.

[0099] The solid unit dosage forms can be of the conventional type.This, the solid form can be a capsule, such as an ordinary gelatin typecontaining the compound of the present invention and a carrier, forexample, lubricants and inert fillers such as, lactose, sucrose, orcornstarch. In another embodiment, these compounds are tableted withconventional tablet bases such as lactose, sucrose, or cornstarch incombination with binders like acacia, cornstarch, or gelatin,disintegrating agents such as, cornstarch, potato starch, or alginicacid, and a lubricant like stearic acid or magnesium stearate.

[0100] The compounds of this invention may also be administered ininjectable dosages by solution or suspension of the compounds of thepresent invention in a physiologically acceptable diluent with apharmaceutical carrier. Such carriers include sterile liquids such aswater and oils, with or without the addition of a surfactant and otherpharmaceutically acceptable adjuvants. Illustrative oils are those ofpetroleum, animal, vegetable, or synthetic origin, for example, peanutoil, soybean oil, or mineral oil. In general,. water, saline, aqueousdextrose and related sugar solution, and glycols such as, propyleneglycol or polyethylene glycol, are preferred liquid carriers,particularly for injectable solutions.

[0101] For use as aerosols the compounds of this invention in solutionor suspension may be packaged in a pressurized aerosol containertogether with suitable propellants, for example, hydrocarbon propellantslike propane, butane, or isobutane with conventional adjuvants. Thecompounds of the present invention also may be administered in anon-pressurized form such as in a nebulizer or atomizer.

[0102] The compounds of the present invention can be used to treat warmblooded animals, birds, and mammals. Examples of such beings includehumans, cats, dogs, horses, sheep, cows, pigs, lambs, rats, mice, andguinea pigs.

[0103] The piperidine derivative compounds of the present invention areprepared by providing a substantially pure regioisomer of the followingformula:

[0104] and then converting the substantially pure regioisomer to thepiperidine derivative compounds of the invention having a keto groupwith a piperidine compound of the formula:

[0105] The resulting piperidine derivative compounds with a keto groupcan be converted by reduction to the above-described piperidinecompounds with a hydroxyl group

[0106] There are several techniques of providing these substantiallypure regioisomers.

[0107] Process One For Producing Substantially Pure Regioisomer

[0108] In one embodiment of the present invention, the substantiallypure regioisomer is formed by initially acylating a starting compound ofthe formula:

[0109] wherein

[0110] R₅ is —OR₆, —N(R₆)₂, and —SR₆, and

[0111] R₆is an alkyl with 1 to 6 carbons,

[0112] with a compound of the formula:

[0113] wherein

[0114] X is a halogen,

[0115] under conditions effective to produce a first mixture ofregioisomers of the formula:

[0116] Such conditions include those conventionally utilized in aFriedel-Crafts acylation reaction catalyzed by, for example, AlCl₃. Thereaction is carried out in a solvent such as, carbon disulfide,tetrachloroethane, or nitrobenzene with carbon disulfide being thepreferred solvent. The reaction is carried out for a time period of ½ to12 hours, preferably 3 to 5 hours, at a temperature of 0 to 25 C.

[0117] The first mixture of regioisomers can be hydrolyzed underconditions effective to form a second mixture of regioisomers of theformula:

[0118] Typically this reaction is carried out by base hydrolysisprocedures which are well known in the art. For example, the firstmixture of regioisomers can be treated with an inorganic base, such as,sodium hydroxide or potassium hydroxide, in an aqueous lower alcoholsolvent. Suitable solvents include aqueous methanol, ethanol,isopropanol, or n-butanol solutions. Hydrolysis is carried out at refluxtemperatures of the solvent for ½ to 12 hours..

[0119] Following such hydrolyzation, the substantially pure regioisomerof the formula:

[0120] is recovered from the second mixture of regioisomers. Suchrecovery is carried out by crystallizing the substantially pureregioisomer salt of the formula:

[0121] wherein

[0122] X⁺ is a Lewis Acid

[0123] Such crystallization is carried out by fractional crystallizationtechniques known in the art. Generally, such procedures involvedissolving the second mixture of regioisomers in a solvent containing asalt at temperatures of 20 C. to the reflux temperature of the solvent.The resulting solution is then slowly cooled to temperatures of −20 to25 C.

[0124] Suitable solvents for fractional crystallization include: alcoholsolvents, like methanol, ethanol, isopropyl alcohol, and n-butanol;ketone solvents, such as acetone or methyl ethyl ketone;ester-containing solvents, like ethyl acetate or isopropyl acetate;ethereal solvents such as tetrahydrofuran; acetonitrile; anddimethylformamide. Ethyl acetate is preferred.

[0125] Suitable salts for fractional crystallization are those where X⁺is an alkali metal salt, like sodium and potassium salts, or, morepreferably, ammonium salts of the form NR₇R₈R₉, where R₇, R₈, and R₉ ishydrogen or a straight or branched alkyl of 1 to 6 carbon atoms whichmay be substituted at any position with a phenyl ring or a substitutedphenyl ring. The ammonium salt can also be cinchonidine, quinine,quinidine, quinuclidine, brucine, thebaine, or cinchonine. Of these saltcomplexes, cinchonidine is preferred.

[0126] The substantially pure regioisomer salt is then isolated byfiltration and converted to the substantially pure regioisomer of theformula:

[0127] by procedures well known in the art. Typically, such conversionis accomplished by treatment with acid.

[0128] Process Two For Producing Substantially Pure Regioisomer

[0129] In another embodiment of the process of the present invention,the substantially pure regioisomer is produced by acylating a startingcompound of the formula:

[0130] wherein

[0131] R₃ is —COOH, —COOalkyl, —CON(alkyl)₂, —COSalkyl where the

[0132] alkyl moieties have 1 to 6 carbon atoms and are straight orbranched with a compound of the formula:

[0133] wherein

[0134] X₁ is a halogen, trialkyl tin, trialkyl borate, triflate, ororganometallic reagents of lithium or magnesium derived from bromine oriodine, with any alkyl groups having 1 to 4 carbon atoms and beingstraight or branched under conditions effective to produce thesubstantially pure regioisomer of the formula:

[0135] This acylation reaction is carried out in a suitable solvent inthe presence of an appropriate catalyst for about 1 to 120 hours and attemperatures of about 0 C. to the reflux temperature of the solvent.Suitable solvents for acylation include: hydrocarbon solvents, such asbenzene, toluene, xylene, or cyclohexane; halogenated hydrocarbons, suchas chlorobenzene, dichloroethane, methylene chloride, chloroform, orcarbon tetrachloride; carbon disulfide; dimethylformamide; etherealsolvents, like tetrahydrofuran and diethylether; or dioxane.

[0136] A variety of catalysts may be utilized when A is hydrogen.Suitable catalysts include palladium catalysts, like palladium chloride,palladium acetate, tetrakis(triphenylphosphine)palladium(0),dichlorobis(triphenylphosphine palladium(II), orbenzylchlorobis(triphenylphosphine)palladium(II); or nickel-phosphinecatalysts. Acylation may also be carried out in the presence of addedlithium chloride or triphenylphosphine. The latter acylation reaction isknown in the art as organometalic cross coupling reactions and areconducted by the general procedures of D. Milstein, et al., J. Org.Chem., 1979, 44, 1613; J. W. Labadie, et al., J. Org. Chem., 1983, 48,434; C. Sahlberg, et al., Tetrahedron Letters, 1983, 24, 5137; D.Milstein, et al., J. Am. Chem. Soc., 1978, 100, 3636; and K. Tamao, etal., Tetrahedron, 1982, 38, 3347.

[0137] Process Three For Producing Substantially Pure Regioisomer

[0138] In another embodiment of the process of the present invention,the substantially pure regioisomer is produced by acylating a startingcompound of the formula:

[0139] wherein

[0140] R₅ is —OR₆, —N(R₆)₂, and —SR₆, and

[0141] R₆ is an alkyl with 1 to 6 carbon atoms

[0142] with a compound of the formula:

[0143] under conditions effective to produce a first mixture ofregioisomers of the formula:

[0144] Typically, such acylation is carried out by a Friedel-Craftsreaction, as described above in Process One for Producing SubstantiallyPure Regioisomers.

[0145] The substantially pure regioisomer salt is recovered byfractional crystallization, isolation, and converting, as describedabove with reference to Process One for Producing Substantially PureRegioisomers.

[0146] Once the substantially pure regioisomer of the present inventionis produced by one of the above (or some other)process, there are anumber of procedures for using that compound to produce the piperidinederivatives of the present invention.

[0147] Process One Of Converting The Substantially Pure Regioisomer toThe Substantially Pure Piperidine Derivative Having A Keto Group

[0148] According to one aspect of the present invention, thesubstantially pure regioisomer can be halogenated under conditionseffective to form a first intermediate compound of the formula:

[0149] wherein X is a halogen.

[0150] Suitable halogens include chlorine, bromine, and iodine. Suitableconditions for carrying out such halogenating include reacting thesubstantially pure regioisomer with a halogen nucleophile and a LewisAcid. The ring opening reaction is carried out in a suitable solvent,optionally in the presence of a catalytic amount of base for about 0.5to 24 hours and a temperature of about −40 degrees C. to the refluxtemperature of the solvent. Suitable halogen nucleophiles include sodiumiodide, sodium bromide, potassium iodide, potassium bromide, cesiumiodide, cesium bromide, trimethylsilyl iodide, manganese iodide, ceriumiodide, magnesium bromide, magnesium iodide, magnesium carbonate,calcium bromide, and calcium iodide. Suitable Lewis Acids includesilicon compounds such as trimethylsilyl chloride and trimethylsilyliodide; aluminum compounds such as aluminum chloride, trimethylaluminum, diethyl aluminum chloride, ethyl aluminum dichloride, anddiethyl aluminum cyanide; magnesium salts; and boron salts. Suitablesolvents for the ring opening reaction include hydrocarbon solvents,such as, benzene, toluene, xylene, or cyclohexane; ethereal solventssuch as ether, tetrahydrofuran, dioxane, or dimethoxyethane; orhalogenated hydrocarbons, such as, chlorobenzene, methylene chloride,carbon tetrachloride, chloroform, or dichloroethane.

[0151] After such halogenation, the first intermediate compound isreacted with a piperidine compound of the formula:

[0152] under conditions effective to form the piperidine derivativecompound having a keto group of the formula:

[0153] This alkylation reaction is carried out in a suitable solventpreferably in the presence of a base and, optionally, in the presence ofa catalytic amount of potassium iodide for about 4 to 120 hours at atemperature of about 70 C. to the reflux temperature of the solvent.Suitable solvents for the alkylation reaction include alcohol solvents,such as, methanol, ethanol, isopropyl alcohol, or n-butanol; ketonesolvents, such as, methyl isobutyl ketone; hydrocarbon solvents, suchas, benzene, toluene, or xylene; halogenated hydrocarbons, such as,chlorobenzene or methylene chloride; or dimethylformamide. Suitablebases for the alkylation reaction include inorganic bases, for example,sodium bicarbonate, potassium carbonate, or potassium bicarbonate ororganic bases, such as a trialkylamine, for example, triethylamine orpyridine, or an excess of the piperidine compound can be used.

[0154] When R₃ is —COOalkyl, the alkylation reaction is followed by basehydrolysis to convert R₃ substituents that are —COOalkyl groups to —COOHgroups. Such base hydrolysis involves treatment of the substantiallypure piperidine derivative with an inorganic base, such as, sodiumhydroxide m an aqueous lower alcohol solvent, such as, aqueous methanol,ethanol, isopropyl alcohol, or n-butanol at reflux temperature for about½ hour to 12 hours.

[0155] Piperidine compounds where each of R₁ and R₂ is hydrogen orwherein R₁ is hydroxy and R₂ is hydrogen are commercially available ormay be prepared according to procedures well known in the art (e.g. F.J. McCarty, C. H. Tilford, M. G. Van Campen, J. Am. Chem. Soc., 1961,26, 4084). Piperidine compounds wherein R₁ and R₂ form a second bondbetween the carbon atoms bearing R₁ and R₂ may be prepared bydehydration of the corresponding compound wherein R₁ is hydroxy byprocedures generally known in the art.

[0156] Second Process For Converting Substantially Pure Regioisomer ToSubstantially Pure Piperidine Derivative Having A Keto Group

[0157] In another embodiment of the present invention, the substantiallypure regioisomer of the formula:

[0158] is reacted directly with a piperidine compound of the formula:

[0159] under conditions effective to form the piperidine derivativecompound having a keto group of the formula:

[0160] This alkylation reaction is carried out in a suitable solventpreferably in the presence of a base and optionally in the presence of aLewis Add such as magnesium, cesium, or calcium salts or trimethylsilylchloride or in the presence of a catalytic amount of potassium iodidefor about 4 to 120 hours at a temperature of about 70 C. to the refluxtemperature of the solvent. Suitable solvents for the alkylationreaction include alcohol solvents, such as, methanol, ethanol, isopropylalcohol, or n-butanol; ketone solvents, such as, methyl isobutyl ketone;hydrocarbon solvents, such as, benzene, toluene, or xylene; andhalogenated hydrocarbons, such as, chlorobenzene or methylene chloride;or dimethylformamide. Suitable bases of the alkylation reaction includeinorganic bases, for example, sodium bicarbonate, potassium carbonate,or potassium bicarbonate or organic bases, such as, a trialkylamine, forexample, triethylamine or pyridine, or an excess of a compound of thepiperidine compound may be used.

[0161] Processes for Reduction of Keto Group in Substantially PurePiperidine Derivative

[0162] As discussed above, the process of the present invention isuseful in producing substantially pure piperidine derivatives witheither a keto group or a hydroxyl group. Derivatives with keto groupscan be converted to similar compounds with hydroxyl groups by reductionreactions which-are well known in the art.

[0163] Reduction can be carried out with sodium borohydride or potassiumborohydride in lower alcohol solvents, such as, methanol, ethanol,isopropyl alcohol, or n-butanol.

[0164] When lithium aluminum hydride or diborane are used as reducingagents, suitable solvents are ethers, for example, diethyl ether,tetrahydrofuran, or dioxane. These reduction reactions are carried outat temperatures ranging from about 0 C. to the reflux temperature of thesolvent, and the reaction time varies from about 0.5 to 8 hours.

[0165] Catalytic reduction may also be employed using, for example,Raney nickel, palladium, platinum or rhodium catalysts in lower alcoholsolvents, such as, methanol, ethanol, isopropyl alcohol or n-butanol oracetic acid or their aqueous mixtures, or by the use of aluminumisopropoxide in isopropyl alcohol. Reduction using sodium borohydride isgenerally preferred over catalytic reduction when forming carboxylicadds or esters. When the starting material is an ester, lithium aluminumhydride is the preferred reducing agent, while diborane is preferredwhen starting with an add.

[0166] When esters with hydroxyl groups have been formed, basehydrolysis can be used to produce a carboxylic acid. Such procedures arewell known and generally involve treatment with an inorganic base, suchas, sodium hydroxide or potassium hydroxide, in an aqueous loweralcoholic solvent,, such as, aqueous methanol, ethanol, isopropylalcohol, or n-butanol. Base hydrolysis is carried out at about thesolvent reflux temperature for about ½ hour to 12 hours.

EXAMPLES Example 1

[0167] Preparation of Ethyl 3- and4-(4-chloro-1-oxobutyl)-α,α-dimethylphenylacetate

[0168] Aluminum chloride (44 g; 033 mol) was added slowly in portions toa solution of freshly distilled 4-chlorobutyryl chloride (17 mL; 0.15mol) in 460 mL of carbon disulfide at −10 C. under a nitrogenatmosphere. The mixture was stirred for 15 minutes, then the coolingbath was removed and the mixture was allowed to warm to ambienttemperature. The mixture was stirred then for 15 minutes more, thencooled again to −10 C. and a solution of ethyl α,α-dimethylphenylacetate (26.6 g; 0.14 mol) in 70 mL of carbon disulfide was addeddropwise. The mixture was maintained with stirring for 3 hr, thenstirred overnight at room temperature.

[0169] The reaction mixture was partitioned between H₂O and CHCl₃. Thecombined organic portions were washed with saturated aqueous NaHCO₃solution, dried over MgSO₄ filtered and concentrated in vacuo. Theresidue was dissolved in CH₂Cl₂ and filtered through a plug of SiO₂,eluting with 10% EtOAc in hexane. Concentration of theproduct-containing fractions afforded 39.4 g of ethyl 3- and4-(chloro-1-oxobutyl)-α,α-dimethylphenylacetate as a mixture of aromaticregioisomers.

Example 2

[0170] Preparation of4-(Cyclopropyl-oxo-methyl)-α,α-dimethylphenylacetic acid

[0171] To a solution of 39.4 g of ethyl 3- and4(chloro-1-oxobutyl)-α,α-dimethylphenylacetate obtained in Example 1dissolved in 800 mL of CH₃OH and 200 mL of H₂O was added 40 g of NaOH.The resulting mixture was refluxed for one hour. The cooled mixture wasthen concentrated in vacuo to remove the CH₃OH. The concentrate wasdiluted with H₂O and washed with two portions of EtOAc. The aqueouslayer was acidified with concentrated HCl and extracted with twoportions of EtOAc. The extracts were dried over MgSO₄ filtered, andconcentrated in vacuo to afford 30.3 g of crude product.

[0172] The crude product was dissolved in 600 mL of EtOAc, 38 g ofcinchonidine was added, and the mixture was stirred overnight. Theresulting solids were filtered and washed with EtOAc and sucked dryunder a rubber dam to afford 25 g of a tan solid.

[0173] The solids were partitioned between EtOAc and 2N HCl. The aqueouslayer was extracted with EtOAc. The combined organics were dried overMgSO₄, filtered, and concentrated in vacuo to afford 10.6 g of an oil(33% from ethyl axo-dimethyl-phenylacetate).

Example 3

[0174] Preparation of 4-(Iodo-1-oxobutyl)-α,α-dimethylphenylacetic acid

[0175] A solution of 10.5 g of4(cyclopropyl-oxo-methyl)-α,α-dimethylphenylacetic acid, prepared inaccordance with Example 2, in 250 mL of CH₂Cl₂ was cooled in an ice-MeOHbath and 25 g of trimethylsilyliodide was then added rapidly viapipette. The mixture was stirred in the ice bath for one hour, warmed toambient temperature, and stirred for one hour. A solution of aqueoussodium bisulfite was then added and the mixture was stirred well. Thephases were partitioned and the aqueous layer was extracted with CH₂Cl₂.The combined organics were washed with saturated aqueous NaCl, driedover MgSO₄ filtered, and concentrated in vacuo to afford 12.6 g (77%) of4-(4iodo-1-oxobutyl)-α,α-dimethylphenylacetic acid.

Example 4

[0176] Preparation of Methyl4-(4-Iodo-1-oxobutyl)-α,α-dimethylphenylacetate

[0177] To a solution of 12.6 g of4-(4-iodo-1-oxobutyl)-α,α-dimethylphenylacetic acid, prepared inaccordance with Example 3, in 100 mL of Et₂O cooled in an ice bath, wasadded 40 mL of ethereal CH₂N₂. The mixture was stirred at 0 C. for fewminutes, then let stand for 2 hr. A few drops of AcOH were added todecompose excess CH₂N₂, then the mixture was filtered and stripped toafford 12.6 g (96%) of methyl4-(4-iodo-1-oxobutyl)-α,α-dimethylphenylacetate.

Example 5

[0178] Preparation of Methyl4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl-1-oxobutyl]-α,α-dimethylphenylacetate

[0179] A solution of 12.6 g of methyl4(4-iodo-1-oxobutyl)-α,α-dimethylphenylacetate, prepared in accordancewith Example 4, in 500 mL of toluene in a one liter three neck flaskwith mechanical stirring was added 8.8 g of4-α,α-diphenyl)piperidinemethanol and 23 g of K₂CO₃ and the mixture wasrefluxed for 7 hr. The cooled reaction mixture was then filtered andconcentrated in vacuo. The residue was dissolved in Et₂O and treatedwith excess ethereal HCl. The mixture was then concentrated to a solid.The solid was treated with EtOAc and collected by filtration. Theproduct was then partitioned between EtOAc and 2N Na₂CO₃. The organicswere dried over MgSO₄ filtered, and concentrated in vacuo to afford 135g (79%) of methyl4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylphenylacetate.

Example 6

[0180] Preparation of Methyl4-[4-[4-Hydroxydiphenylmethyl)-1-piperidinyl-1-hydroxybutyl]-α,α-dimethylphenylacetate

[0181] A solution of 135 g of methyl4-[4-[4-(hydroxydiphenylmethyl)-piperidinyl]-oxobutyl]-α,α-dimethylphenylacetate,prepared in accordance with Example 5, in 250 mL of CH₃OH was cooled inan ice- CH₃OH bath and 1.8 g of NaBH₄ was added in portions. After 1 hr,the mixture was concentrated to a solid. The residue was partitionedbetween EtOAc and saturated aqueous NaHCO₃. The aqueous portion wasextracted with EtOAc. The combined organics were washed with saturatedaqueous NaCl, dried over MgSO₄, filtered, and concentrated in vacuo to-afford 9.5 g (70%) of methyl4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylphenylacetateas a foam.

Example 7

[0182] Preparation of4-[4-[4-Hydroxydiphenylmethyl)-1-piperdindyl]-1-hydroxybutyl]-α,α-dimethylphenylaceticAcid

[0183] To a solution of 95 g ofmethyl-4-[4-[4-(hydroxydiphenylmethyl-1-piperidinyl]-1-hydroxybutyl]-α,α-diethylphenylacetate,prepared in accordance with Example 6, in 300 mL of CH,,H and 150 mL ofH₂O was added 10 g of NaOH. The mixture was refluxed for 1 hr, thencooled. The CH₃OH was removed in vacuo. The concentrate was diluted withH₂O and CHCl₃ and the pH adjusted to approximately 55 to 6.0. The phaseswere separated and the aqueous phase was extracted with CHCl₃. Thecombined organics were dried over MgSO₄ filtered, and stripped to afford9.0 g of crude product.

[0184] The crude product was dissolved in CH₂Cl₂ and chromatographed onDavisil Grade 633 SiO₂ eluting with a gradient of CHCl₃, to 10% CHO₃OHin CHCl₃, to 25% CH₃OH in CHCl₃. The product containing fractions wereconcentrated to afford 5.2 g of white crystals. An analytical sample wasprepared by treatment of the product with EtOAc, mp 199-203 C. Calc. forC₃₂H₃₉NO₄: C, 76.62; H, 7.84; N, 2.79. Found: C, 76.24; H, 7.76; N,2.75.

Example 8

[0185] Preparation of Methyl4-[4-[4-(Bis(4-methylphenyl)hydroxymethyl)-1-piperidinyl]-1-oxobutyl-α,α-dimethylphenylacetate

[0186] To a solution of 6.4 g (0.017 mol) of methyl4-(4-iodo-1-oxobutyl)-α,α-dimethylphenylacetate, prepared in accordancewith Example 4, in 500 mL of toluene in a one liter round bottom flaskequipped with a mechanical stirrer was added 5.1 g (0.017 mol) of4-(α,α-bis(4-methylphenyl)-piperidinemethanol, followed by 11.8 g (0.086mol) of solid potassium carbonate. The solution was heated to reflux for24 hr. After cooling, the mixture was filtered and the toluene wasremoved in vacuo. The residue was partitioned between ethyl acetate and2 N sodium bicarbonate solution. The aqueous layer was extracted twicewith ethyl acetate, the combined organic layers were dried with sodiumsulfate and the ethyl acetate was removed in vacuo to provide 6.8 g(73%) of methyl4-[4-[4-(bis(4-methylphenyl)hydroxymethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylphenylacetateas a viscous, dark colored oil.

Example 9

[0187] Preparation of Methyl4-[4-[4-(Bis(4-Methylphenyl)hydroxymethyl-1-piperidinyl]-4-hydroxybutyl]-α,α-dimethylphenylaceate

[0188] To a −10 C. solution of 6.8 g (0.013 mol) of methyl4-[4-[4-bis(4-methylphenyl)hydroxymethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylphenylacetate,prepared in accordance with Example 8, in 150 mL of methanol in a 500 mLround bottom flask equipped with a mechanical stirrer was slowly added0.86 g (0.023 mol) of sodium borohydride, and the reaction was stirredfor 2 hr. The methanol was removed in vacuo and the residue waspartitioned between ethyl acetate and aqueous sodium bicarbonatesolution. The aqueous layer was extracted with ethyl acetate, thecombined organic layers were dried with sodium sulfate, and the ethylacetate was removed in vacuo to provide 6.9 g of a dark colored foam.The resultant material was purified by column chromatography (Davisilgrade 633 silica gel, packed in methylene chloride, material applied inchloroform, and eluted with a gradient of 2% methanol to methylenechloride to 5% methanol to methylene chloride) to afford 5.3 g (77%) ofmethyl4-[4-[4-(bis(4-methylphenyl)hydroxymethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylphenylacetate.

Example 10

[0189] Preparation of4-[4-[4-(Bis(4-methylphenyl)hydroxymethyl)-1-piperidinyl-1-hydroxybutyl]-α,α-dimethylphenylaceticAcid

[0190] To 350 mL of methanol in a 1 L round bottom flask equipped with amechanical stirrer was added 5.3 g (9.8 mmol) of methyl4-[4-[4-(bis(4-methylphenyl)hydroxymethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylphenylacetate,prepared in accordance with Example 9, 5.1 g (0.13 mol) of solid sodiumhydroxide, and 100 mL of water. The mixture was heated to reflux for 3hr. After cooling, the methanol was removed in vacuo, and 6 Nhydrochloric acid was added dropwise until the solution was no longerbasic (pH=7). The solution was extracted three times with ethyl acetate.The organic layers were combined and a white crystalline solidprecipitated out of solution. The solid was washed with ether to provide1.8 g (34%) of[4-[4-4-bis(4-methylphenyl)hydroxymethyl)-1-piperidinyl]-1-hydroxybutyl)-α,α-dimethylphenylaceticacid, as the dihydrate, mp 208-215 C. Analysis. Calcd forC₃₄H₄₃NO₄-2(H₂O): C, 72.18;- H, 8.37; N, 2.47. Found: C, 72.02; H, 836;N, 2.41.

Example 11

[0191] Preparation of 4-(1-Hydroxy-4-iodobutyl)-α,α-dimethylphenylaceticacid

[0192] To a solution of 50 mg of4-(4-iodo-1-oxobutyl)-α,α-dimethylphenylacetic acid, preparedin-accordance with Example-3, in 3 mL of methanol was added 50 mg ofNaBH₃. The mixture was stirred for 30 minutes, acidified with 2N HCl,and the methanol removed in vacuo. The concentrate was extracted withEtOAc. The organics were dried over Na₂SO₄, filtered, and concentratedto afford 40 mg of 4-(1-hydroxy-4-iodobutyl)-α,α-dimethylphenylaceticacid.

Example 12

[0193] Preparation of4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylphenylaceticacid

[0194] A mixture of 800 mg of4-(4-iodo-1-oxobutyl)-α,α-dimethylphenylacetic acid, prepared inaccordance with Example 3, 800 mg of 4-(α,α-diphenyl)piperidinemethanol,and 2.4 g of K₂CO₃ in 25 mL of toluene was stirred for 48 hours at roomtemperature. The mixture was concentrated in vacuo. The residue wastreated with EtOAc, filtered, and concentrated to afford4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylphenylaceticacid.

Example 13

[0195] Preparation of4-[4-[4-Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylphenylaceticAcid

[0196] A mixture of4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylphenylaceticacid, prepared in accordance with Example 12, and 300 mg of NaBH₄ in 25mL of CH₃OH was stirred overnight at room temperature. The mixture wasthen concentrated in vacuo. The residue was partitioned between EtOAcand H₂O. The aqueous portion was treated with concentrated HCl until pH6, then extracted with EtOAc. The organics were concentrated in vacuo.The residue was-dissolved in EtOAc, filtered, and concentrated in vacuoto an oil. The oil was dissolved in CH₃OH and concentrated to a solid.The solid was slurried with EtOAc, filtered, and rinsed with EtOAc toafford4-[4-[4-hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylphenylaceticacid.

[0197] Although the invention has been described in detail for thepurpose of illustration, it is understood that such detail is solely forthat purpose, and variations can be made therein by those skilled in theart without departing from the spirit and scope of the invention whichis defined by the following claims.

What is claimed:
 1. A process of preparing a piperidine derivativecompound of the formula:

wherein R₁ is hydrogen or hydroxy; R₂ is hydrogen; or R₁ and R₂ takentogether form a second bond between the carbon atoms bearing R₁ and R₂;R₃ is —COOH or —COOR₄; R₄ has 1 to 6 carbon atoms; A, B, and D are thesubstituents of their rings, each of which may be different or the same,and are selected from the group consisting of hydrogen, halogens, alkyl,hydroxy, alkoxy, or other substituents said process comprising:providing a substantially pure regioisomer of the following formula:

and converting the substantially pure regioisomer to the piperidinederivative compound with a piperidine compound of the formula:


2. A process according to claim 1, wherein said providing comprises:acylating a starting compound of the formula:

wherein R₅ is —OR₆, —N(R₆)₂, and —SR₆, and R₆ is an alkyl with 1 to 6carbons, with a compound of the formula:

wherein X is a halogen, under conditions effective to produce a firstmixture of regioisomers of the formula:

hydrolyzing the first mixture of regioisomers under conditions effectiveto form a second mixture of a regioisomers of the formula:

recovering from the second mixture of regioisomers the substantiallypure regioisomer of the formula:


3. A process according to claim 2, wherein said recovering comprises:crystallizing from the second mixture of regioisomers a substantiallypure regioisomer salt of the formula:

wherein X⁺ is a Lewis Acid; isolating the substantially pure regioisomersalt; and converting the substantially pure regioisomer salt to thesubstantially pure regioisomer of the formula:


4. A process according to claim 3, wherein X⁺ is an alkali metal salt oran ammonium salt of the form NR₇R₈R₉ wherein R₇, R₈, and R₉ areindividually hydrogen or a straight or branched alkyl of 1 to 6 carbonatoms, or an alkyl substituted at any position with a phenyl ring or asubstituted phenyl ring.
 5. A process according to claim 4, wherein X⁺is cinchonidine and A is hydrogen.
 6. A process according to claim 2,wherein said acylating is carried out by a Friedel-Crafts reaction usingAlCl₃ catalyst.
 7. A process according to claim 1, wherein saidproviding comprises: acylating a starting compound of the formula:

with a compound of the formula

wherein X₁ is a halogen, trialkyl tin triflate, or substituents usefulin a organometalic coupling reactions under conditions effective toproduce the substantially pure regioisomer of the formula:


8. A process according to claim 1, wherein said providing comprises:acylating a starting compound of the formula:

wherein R₅ is —OR₆, —N(R₆)₂, and —SR₆ and R₆ is an alkyl with 1 to 6carbon atoms with a compound of the formula:

under conditions effective to produce a first mixture of regioisomers ofthe formula:

hydrolyzing the first mixture of regioisomers under conditions effectiveto form a second mixture of regioisomers of the formula:

and recovering from the second mixture of regioisomers the substantiallypure regioisomer of the following formula:


9. A process according to claim 8, wherein said recovering comprises:crystallizing a substantially pure regioisomer salt of the formula:

wherein X⁺ is a Lewis Acid from the second mixture of regioisomers;isolating the substantially pure regioisomer salt; and converting thesubstantially pure regioisomer salt to the substantially pureregioisomer of the formula:


10. A process according to claim 9, wherein X⁺ is an alkali metal saltor an ammonium salt of the form NR₇R₈R₉, wherein R₇, R₈, and R₉ ishydrogen or a straight or branched alkyl of 1 to 6 carbon atoms, or analkyl substituted at any position with a phenyl ring or a substitutedphenyl ring.
 11. A process according to claim 10 wherein X⁺ iscinchonidine and A is hydrogen.
 12. A process according to claim 8,wherein said acylating is carried out with a catalyst containingpalladium, nickel, or mixtures thereof.
 13. A process according to claim1 further comprising: reducing the piperidine derivative underconditions effective to form a hydroxylated piperidine derivative of theformula:


14. A process according to claim 13, wherein the hydroxylated piperidinederivative has the formula:


15. A process according to claim 13, wherein the hydroxylated piperidinederivative has the formula:


16. A process according to claim 1, wherein said converting comprises:halogenating the substantially pure regioisomer of the followingformula:

under conditions effective to form a first intermediate compound of theformula:

wherein X is a halogen and reacting the first intermediate compound witha piperidine compound of the formula:

under conditions effective to form the piperidine derivative of thefollowing formula:


17. A process according to claim 1, wherein said converting comprises:reacting the substantially pure regioisomer of the following formula:

with a piperidine compound of the formula:

under conditions effective to form the piperidine derivative of theformula:


18. A process according to claim 1, wherein the piperidine derivativehas the formula:


19. A process according to claim 1, wherein the piperidine derivativehas the formula:


20. A substantially pure piperidine derivative compound of the formulae:

wherein R₁ is hydrogen or hydroxy; R₂ is hydrogen; or R₁ and R₂ takentogether form a second bond between the carbon atoms bearing R₁ and R₂;R₃ is —COOH or —COOR₄; R₄ is an alkyl with 1 to 6 carbon atoms; A, B,and D can be one or more different substituents of their rings and areindividually hydrogen, halogens, alkyl, hydroxy, alkoxy, or othersubstituents. or a salt thereof.
 21. A substantially pure piperidinederivative compound according to claim 20, wherein the compound has theformula:


22. A substantially pure piperidine derivative compound according toclaim 20, wherein the compound has the formula:


23. A substantially pure piperidine derivative compound according toclaim 20, wherein the compound has the formula:


24. A substantially pure piperidine derivative compound according toclaim 23, wherein the compound has the formula:


25. A substantially pure piperidine derivative compound according toclaim 20, wherein the compound has the formula:


26. A substantially pure piperidine derivative compound according toclaim 25, wherein the compound has the formula:


27. A pharmaceutical composition comprising: a pharmaceutical carrierand the substantially pure piperidine derivative compound according toclaim
 20. 28. A pharmaceutical composition according to claim 27,wherein said substantially pure piperidine derivative compound ispresent in an effective antiallergic amount.
 29. A pharmaceuticalcomposition according to claim 27, wherein said composition consistsessentially of said substantially pure piperidine derivative compound.30. A method of treating allergic reactions in a patient comprising:administering to the patient said pharmaceutical composition accordingto claim 27 in an effective amount.
 31. A compound of the formula:

wherein R₃ is —COOH or —COOR₄; R₄ is an alkyl with 1 to 6 carbon atoms;A is the substituents of its ring, each of which may be different or thesame, and are selected from the group consisting of hydrogen, halogens,alkyl, hydroxy, alkoxy, or other substituents.